The aryl hydrocarbon (Ah) receptor (AhR) is a ligand inducible transcription factor, a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon binding to its ligand, AhR mediates or interacts with a series of biological processes as well as some adverse effects including cell division, apoptosis, cell differentiation, actions of estrogen and androgen, adipose differentiation, hypothalamus actions, angiogenesis, immune system homeostasis, teratogenicity, tumorigenicity, chloracne, wasting syndrome, and actions of other hormonal systems beside the expression of genes of P450 family and others. The liganded receptor participates in biological processes through translocation from cytoplasm into nucleus, heterodimerization with another factor named Ah receptor nuclear translocator, attachment of the heterodimer to the regulatory region termed Ah response element of genes under AhR regulation, and then either enhancement or inhibition of transcription of those genes.
The AhR happens to be able to bind, with different affinities, to several groups of exogenous chemicals (thus artificial ligands) such as polycyclic aromatic hydrocarbons exemplified by 3-methylchoranthrene (3-MC) and halogenated aromatic hydrocarbons typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The receptor system has been studied so far with its artificial ligands. While these studies helped greatly in advancing our understanding toward the receptor system, thorough elucidation of the physiological roles the system plays and the potential therapeutic benefits the system may offer are impossible without the identification of AhR physiological ligand. As the first step toward this goal, an endogenous ligand for the receptor has been identified. The endogenous ligand, or physiological ligand, or natural hormone, for the AhR was identified as 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (short for ITE).
Even though most of the artificial ligands for AhR are environmental toxins and thus cannot be used as therapeutic agents, for the purpose of understanding functions of liganded AhR, its artificial ligands such as TCDD, 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), 8-methyl-1,3,6-trichlorodibenzofuran (8-MCDF), and those derived from indole or tryptophan were used to reveal that the liganded AhR was able to inhibit the metastasis of prostate tumors in a strain of transgenic mice and the growth of carcinogen induced rat mammary tumors, human breast tumor cell xenografts, and tumors caused by gene mutations.
As a natural ligand for AhR, ITE is an excellent agent in targeting precisely and specifically the receptor. The consequence of the targeting, however, is unpredictable from the behaviors of those artificial ligands for AhR, with some results demonstrating anticancer potentials while others tumor initiation, promotion, and progression. As disclosed in a U.S. patent application Ser. No. 13/503,657, it is impossible to predict meaningfully what a newly identified ligand for AhR might do in terms of cancer biology. The same application also explained that, as an antiangiogenic agent, ITE would not be automatically qualified as an effective anticancer agent, either.
There are two serious problems with current cancer therapies in the market. The first is side effects and toxicity. The second is efficacy. Consequently, cancer is still the second leading cause of death in the United States and areas of the world.
The majority of current therapeutic agents for cancer, in both cytotoxic and noncytotoxic categories, are chemicals foreign to the human body. As a result, the body tries to reject the agents using metabolic methods available. Since the human body does not have a natural and safe way of metabolizing those foreign chemicals, some nonspecific oxidation reactions then are used as major means of metabolism. The consequence is that the metabolic processes generate chemically active intermediates or radicals, which will assault also normal cellular substances including, but not limited to, that of immune system's in the body, leading to side effects, toxicity, and weakened immune system. Since most of these agents were designed by humans, not nature, they have very high chances to bind to and interact with other cellular factors (including, but not limited to, receptors, enzymes, other proteins) than their expected targets in the body. These “off-target” bindings and interactions account for opportunities for side effects.
Thus, the effectiveness of cytotoxic agents for cancer therapy is limited by their indiscriminate toxicity to normal cells and tissues including, but not limited to, that of immune system's. The weakened immune system makes it impossible to launch an organized assault on cancer cells. The efficacy of noncytotoxic agents, which target specific functions important for the survival of cancer cells, is limited by their single mechanism based strategy. An important hallmark of cancer, however, is their constant genetic changes or mutations. Once a cancer cell changes into a state that it is no longer dependent on a specific function a therapeutic agent targets for survival, the efficacy of the agent will then be lost.
Therefore, there is an unmet medical need to develop a method of cancer treatment with fewer side-effects and higher efficacy, in addition to find methods to protect normal cells from injuries caused by cancer treatment. Further, it is also desirable to development methods of cancer treatment that can alleviate the complication as disclosed herein.